NM_000518.5(HBB):c.51del (p.Lys18fs) AND Beta-thalassemia HBB/LCRB

Germline classification:: Pathogenic (2 submissions)
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003227603.10

Allele description [Variation Report for NM_000518.5(HBB):c.51del (p.Lys18fs)]

NM_000518.5(HBB):c.51del (p.Lys18fs)

Genes:

LOC106099062:HBB recombination region [Gene]
HBB:hemoglobin subunit beta [Gene - OMIM - HGNC]
LOC107133510:origin of replication at HBB [Gene]

Variant type:

Deletion

Cytogenetic location:

11p15.4

Genomic location:

Preferred name:

NM_000518.5(HBB):c.51del (p.Lys18fs)

Other names:

CD 16 GGC>GG-

HGVS:

NC_000011.10:g.5226971del
NG_000007.3:g.70645del
NG_042296.1:g.502del
NG_046672.1:g.4906del
NG_059281.1:g.5101del
NM_000518.5:c.51delMANE SELECT
NP_000509.1:p.Lys18fs
LRG_1232t1:c.51del
HBB:c.51delC
LRG_1232:g.5101del
LRG_1232p1:p.Lys18fs
NC_000011.9:g.5248201del
NC_000011.9:g.5248201delG
NM_000518.4:c.51del
NM_000518.4:c.51delC
NM_000518.5:c.51delCMANE SELECT
p.Lys18fs

Protein change:

K18fs

Links:

Genetic Testing Registry (GTR): GTR000500319; HBVAR: 799; OMIM: 141900.0323; dbSNP: rs35662066

NCBI 1000 Genomes Browser:

rs35662066

Molecular consequence:

NM_000518.5:c.51del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Beta-thalassemia HBB/LCRB
Identifiers:: MONDO: MONDO:0013517; MedGen: CN322236; OMIM: 613985

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003925064	Lifecell International Pvt. Ltd	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21389146, 25741868
SCV004046932	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003925064

Lifecell International Pvt. Ltd

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004046932

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
Asian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mechanism of escape from nonsense-mediated mRNA decay of human beta-globin transcripts with nonsense mutations in the first exon.

Neu-Yilik G, Amthor B, Gehring NH, Bahri S, Paidassi H, Hentze MW, Kulozik AE.

RNA. 2011 May;17(5):843-54. doi: 10.1261/rna.2401811. Epub 2011 Mar 9.

PubMed [citation]

PMID:: 21389146
PMCID:: PMC3078734

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Lifecell International Pvt. Ltd, SCV003925064.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian	1	not provided	not provided	clinical testing	PubMed (2)

Description

A Heterozygous Frameshift variant c.51delC in Exon 1 of the HBB gene that results in the amino acid substitution p.Lys18fs*2 was identified. The observed variant has a minor allele frequency of 0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variation ID: 15414).The variant has been previously reported by Neu-Yilik G, et al., 2011. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004046932.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The frameshift variant has been reported previously in homozygous and compound heterozygous state in patients affected with beta-thalassemia (Krugluger W. et al., 2002; Yasmeen H. et al., 2016). The p.Lys18ArgfsTer2 variant is reported with the allele frequency (0.003%) in the gnomad and novel in 1000 genome database. It has been submitted to ClinVar as a Pathogenic variant. This variant causes a frameshift starting with codon Lysine 18, changes this amino acid to Arginine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Lys18ArgfsTer2. The variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant , the molecular diagnosis of recessive thalassemia is not confirmed.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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